The subject invention relates to novel N-(4-carbamimidoyl-phenyl)-glycine derivatives.
The subject invention provides compounds of the formula: 
wherein
R1 is alkyl;
R2 is hydrogen, hydroxyalkoxy, alkoxycarbonyloxyalkoxy, or halogenalkoxycarbonyloxyalkoxy;
R3 is hydrogen, alkoxy, or heterocycloalkyloxy;
R4 is hydrogen or the residue of an ester group which is cleavable under physiological conditions;
R5 is hydrogen, hydroxy, alkoxycarbonyl, halogenalkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, alkoxyalkoxycarbonyl, cycloalkyloxycarbonyl, alkynyloxycarbonyl, 5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxycarbonyl, arylcarbonyloxy, alkylaminocarbonyloxy, arylaminocarbonyloxy, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, or arylaminocarbonyl; and
X is F, Cl, or Br;
or a hydrate or solvates thereof, or a physiologically acceptable salt thereof or a physiologically acceptable ester thereof,
with the provisio that the compound of formula I is not selected from the group consisting of:
(RS)-(4-carbamimidoyl-phenylamino)-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid ethyl ester,
(RS)-(4-carbamimidoyl-phenylamino)-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid,
(RS)-(4-carbamimidoyl-phenylamino)-(2-fluoro-3,5-dimethoxy-phenyl)-acetic acid, and
(RS)-(4-carbamimidoyl-phenylamino)-(2-fluoro-3,5-dimethoxy-phenyl)-acetic acid ethyl ester.
Certain preferred compounds are where R1 is ethyl or where only one of R2 and R3 is hydrogen. Other compounds are where R2 is hydrogen, or hydroxyalkoxy, or 2-hydroxy-ethoxy, or alkoxycarbonyloxyalkoxy, or halogenalkoxycarbonyloxyalkoxy, or alkoxycarbonyloxyalkoxy, or halogenalkoxycarbonyloxyalkoxy, for exampe 2-(2,2,2-trichloro-ethoxycarbonyloxy)-ethoxy.
R3 can be hydrogen, or alkoxy, for example ethoxy, or heterocycloalkyloxy, for example tetrahydrofuran-3-yloxy. It is also preferred where R4 is hydrogen, alkyl, or aryl-alkyl. Where R4 is alkyl, preferred groups include ethyl, iso-propyl, butyl, or iso-butyl. A preferred aryl-alkyl is benzyl.
For R5, hydrogen, hydroxy, ethoxycarbonyl, 2,2,2-trichloro-ethoxycarbonyl, methoxycarbonyl, 4-fluoro-phenyloxycarbonyl, benzyloxycarbonyl, 2-methoxy-ethoxycarbonyl, 2-isopropyl-5-methyl-cyclohexyloxycarbonyl, prop-2-ynyloxycarbonyl, 5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxycarbonyl, benzoyloxy, ethylaminocarbonyloxy, phenylaminocarbonyloxy, benzoyl, 3-fluoro-benzoyl, 4-fluoro-benzoyl, 2,4-difluoro-benzoyl, 3,4-dimethoxy-benzoyl, 3,5-dimethoxy-benzoyl, 4-methyl-benzoyl, 4-trifluoromethyl-benzoyl, phenylaminocarbonyl, or isobutoxycarbonyl are preferred. While each of these substituents is useful, another grouping is where R5 is alkoxycarbonyl, halogenalkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, alkoxyalkoxycarbonyl, cycloalkyloxycarbonyl, alkynyloxycarbonyl, 5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxycarbonyl, arylcarbonyloxy, alkylaminocarbonyloxy, arylaminocarbonyloxy, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, or arylaminocarbonyl. A further subset is where R5 is alkoxycarbonyl, halogenalkoxycarbonyl, alkoxyalkoxycarbonyl, cycloalkyloxycarbonyl, alkynyloxycarbonyl, alkylaminocarbonyloxy, or alkylcarbonyl. R5 may also be 2,2,2-trichloro-ethoxycarbonyl, or alkylaminocarbonyloxy, or a substituent selected from the group consisting of aryloxycarbonyl, arylalkoxycarbonyl, arylaminocarbonyloxy, arylcarbonyl, and arylaminocarbonyl. Specific favored R5 substituents include benzoyl, or alkylaminocarbonyloxy, or arylcarbonyloxy or arylaminocarbonyloxy, or 5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxycarbonyl, or heteroarylcarbonyl.
While the halogens recited above are all effective as X, flourine is currently preferred.
The subject invention further provides compounds according to claim 1, wherein the compound is of the formula: 
wherein R1, R2, R3, R4, R5, and X are as defined above.
Other convenient groupings are where R3 is hydrogen or heterocycloalkyloxy, R4 is aryl-alkyl, and R5 is hydroxy, alkoxycarbonyl, halogenalkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, alkoxyalkoxycarbonyl, cycloalkyloxycarbonyl, alkynyloxycarbonyl, 5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxycarbonyl, arylcarbonyloxy, alkylaminocarbonyloxy, arylaminocarbonyloxy, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, or arylaminocarbonyl. X is conveniently Cl, or Br.
The subject invention also provides compounds of the formula: 
wherein
R1 is alkyl;
R2 is hydrogen, hydroxyalkoxy, alkoxycarbonyloxyalkoxy, or halogenalkoxycarbonyloxyalkoxy;
R3 is hydrogen, alkoxy, or heterocycloalkyloxy;
R4 is hydrogen or the residue of an ester group which is cleavable under physiological conditions; and
X is F, Cl, or Br.
Although various combinations of R1, R2, R3, R4, R5 and X have been set out above, all combinations of these substituents are possible and are intended to be covered by this description as if specifically written out.
The subject invention will now be described in terms of its preferred embodiments. These embodiments are set foth to aid in understanding the invention but are not to be construed as limiting.
The invention is concerned with novel N-(4-carbamimidoyl-phenyl)-glycine derivatives of the formula I 
wherein
R1 represents alkyl,
R2represents hydrogen, hydroxyalkoxy, alkoxycarbonyloxyalkoxy, or halogenalkoxycarbonyloxyalkoxy,
R3 represents hydrogen, alkoxy, or heterocycloalkyloxy,
R4 represents hydrogen or the residue of an ester group which is cleavable under physiological conditions;
R5 represents hydrogen, hydroxy, alkoxycarbonyl, halogenalkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, alkoxyalkoxycarbonyl, cycloalkyloxycarbonyl, alkynyloxycarbonyl, 5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxycarbonyl, arylcarbonyloxy, alkylaminocarbonyloxy, arylaminocarbonyloxy, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, or arylaminocarbonyl,
X represents F, Cl, or Br,
as well as hydrates or solvates and/or physiologically acceptable salts thereof and/or physiologically acceptable esters thereof,
with the provisio that said compound of formula I is not selected from the group consisting of:
(RS)-(4-carbamimidoyl-phenylamino)-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid ethyl ester,
(RS)-(4-carbamimidoyl-phenylamino)-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid,
(RS)-(4-carbamimidoyl-phenylamino)-(2-fluoro-3,5-dimethoxy-phenyl)-acetic acid, and
(RS)-(4-carbamimidoyl-phenylamino)-(2-fluoro-3,5-dimethoxy-phenyl)-acetic acid ethyl ester.
Further, the invention is concerned with a process for the manufacture of the above compounds, pharmaceutical preparations which contain such compounds as well as the use of these compounds for the production of pharmaceutical preparations.
Examples of physiologically usable salts of these compounds of formula I are salts with physiologically compatible mineral acids, such as hydrochloric acid, sulphuric acid, sulphurous acid or phosphoric acid; or with organic acids, such as methanesulphonic acid, p-toluenesulphonic acid, acetic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. The term xe2x80x9cphysiologically acceptable saltsxe2x80x9d refers to such compounds.
Examples of physiologically acceptable esters are esters of the compounds of formula I, in which hydroxy groups have been converted to the corresponding esters with inorganic or organic acids such as nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like, which are non toxic to living organisms. The term xe2x80x9cphysiologically acceptable estersxe2x80x9d refers to such compounds.
The compounds of formula I can be solvated, especially hydrated. The terms xe2x80x9csolvatesxe2x80x9d and xe2x80x9chydratesxe2x80x9d refer to compounds of formula 1 which additionally comprise solvent molecules or, in the case of hydrates, water molecules respectively. The hydration can take place in the course of the manufacturing process or can occur gradually as a consequence of hygroscopic properties of an initially anhydrous compound of formula I.
The compounds of formula I have at least one asymmetric C atom and can therefore exist as an enantiomeric mixture, diastereomeric mixture or as optically pure compounds. Compounds of formula I can exist in tautomeric forms and the invention encompasses all such tautomeric forms.
In the scope of the present invention xe2x80x9calkylxe2x80x9d, alone or in combination with other groups, such as in alkoxy, alkoxycarbonyl etc., denotes a straight-chain or branched hydrocarbon residue containing 1-6, preferably 1-4 carbon atoms, such as, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, tert-butyl and iso-butyl. Alkyl groups can be substituted, e.g. with one ore more halogen atoms, preferrably with chlorine, e.g. 2,2,2-trichloroethyl. Such groups are referred to as xe2x80x9chalogenalkylxe2x80x9d. Alkyl groups can also be substituted with other groups such as e.g. hydroxy, e.g. hydroxyethyl.
The term xe2x80x9calkoxyxe2x80x9d stands for the group alkyl-O- with alkyl as defined above, e.g. methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy.
The term xe2x80x9calkynylxe2x80x9d, alone or in combination with other groups, stands for a straight-chain or branched hydrocarbon residue containing a triple bond and up to 6, preferably up to 4 C-atoms such as e.g. ethynyl, butynyl or prop-2-ynyl.
The term xe2x80x9ccycloalkylxe2x80x9d stands for a cyclic alkyl group of three to six carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Such cyclic alkyl groups can optionally be substituted by one ore more substituents such as e.g. alkyl, halogen, or alkoxy with alkyl being preferred.
The term xe2x80x9ccycloalkoxyxe2x80x9d or xe2x80x9ccycloalkyloxyxe2x80x9d denotes a cycloalkyl group which is bonded via an oxy (xe2x80x94Oxe2x80x94) group, such as e.g. cyclopentyloxy or cyclohexyloxy.
The term xe2x80x9cheterocycloalkylxe2x80x9d stands for a cyclic alkyl group of three to six carbon atoms which can contain 1 or 2 atoms selected from nitrogen, oxygen or sulphur such as e.g. tetrahydrofuran, pyrrolidine, morpholine, with tetrahydrofuran being preferred. Heterocycloalkyl groups can exhibit a substitution pattern as described for cycloalkyl.
The term xe2x80x9carylxe2x80x9d, alone or in combination, such as in aryloxy, arylalkyl etc. denotes a carbocyclic, aromatic residue such as phenyl, naphthyl or indanyl, preferably phenyl and naphthyl, especially phenyl, which can be substituted, e.g. by halogen, such as bromine, fluorine or chlorine, alkyl, such as methyl, ethyl, propyl or butyl, halogenalkyl, such as trifluoromethly, alkoxy, such as methoxy, ethoxy or propoxy, hydroxy, nitro, amino, mono- or di-alkyl-amino, phenyl, phenoxy, COOH or COO-alkyl, such as COOCH3 or COOC2H5. Preferred substituents are alkoxy, halogen, or alkyl, with fluorine being more preferred. Examples of arylalkyl groups are benzyl, phenethyl, mono- or dimethoxy-benzyl, aminobenzyl or nitrobenzy, with benzyl being preferred, examples of aryloxy groups are phenoxy or methoxycarbonyl-phenoxy, with phenoxy being preferred and examples of arylalkyloxy groups are benzyloxy, methoxy-benzyloxy and phenethoxy, with benzyloxy being preferred.
The term xe2x80x9cheteroarylxe2x80x9d refers to an aromatic 5- or 6-membered ring which can contain 1 or 2 atoms selected from nitrogen, oxygen or sulphur such as furyl, pyridyl, 1,2-, 1,3- and 1,4-diazinyl, thiophenyl, isoxazolyl, oxazolyl or imidazolyl. A heteroaryl group may have a substitution pattern as described earlier in connection with the term xe2x80x9carylxe2x80x9d.
The term xe2x80x9chalogenxe2x80x9d stands for fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine and more preferably fluorine.
Examples of ester groups cleavable under physiological conditions denoted by R4 are alkyl; hydroxyalkyl, such as e.g. hydroxyethyl; aryl-alkyl, morpholinoethyl; tetrahydropyranyl; alkoxycarbonyl-alkyl, such as tert.-butoxycarbonylmethyl (pivoxyl); alkoxycarbonyloxyalkyl, such as 1-(ethoxycarbonyloxy)ethyl, hexyloxycarbonyloxyalkyl (hexetil) and 1-isopropyloxycarbonyloxy)ethyl (proxetil); alkylcarbonyloxyalkyl, such as 1-acetoxyethyl (axetil), 1-(pivaloyloxy)ethyl and 1-(cyclohexylacetoxy)ethyl; dialkylaminocarbonylmethylene; morpholino-4-yl-carbonylmethylene. Preferred ester groups are methyl, ethyl, iso-propyl, butyl, iso-butyl or benzyl.
In detail, the present invention relates to compounds of formula I 
wherein
R1 represents alkyl,
R2 represents hydrogen, hydroxyalkoxy, alkoxycarbonyloxyalkoxy, or halogen alkoxycarbonyloxyalkoxy,
R3 represents hydrogen, alkoxy, or heterocycloalkyloxy,
R4 represents hydrogen or the residue of an ester group which is cleavable under physiological conditions;
R5 represents hydrogen, hydroxy, alkoxycarbonyl, halogenalkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, alkoxyalkoxycarbonyl, cycloalkyloxycarbonyl, alkynyloxycarbonyl, 5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxycarbonyl, arylcarbonyloxy, alkylaminocarbonyloxy, arylaminocarbonyloxy, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, or arylaminocarbonyl,
X represents F, Cl, or Br,
as well as hydrates or solvates and/or physiologically acceptable salts thereof and/or physiologically acceptable esters thereof,
with the provisio that said compound of formula I is not selected from the group consisting of:
(RS)-(4-carbamimidoyl-phenylamino)-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid ethyl ester,
(RS)-(4-carbamimidoyl-phenylamino)-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid,
(RS)-(4-carbamimidoyl-phenylamino)-(2-fluoro-3,5-dimethoxy-phenyl)-acetic acid, and
(RS)-(4-carbamimidoyl-phenylamino)-(2-fluoro-3,5-dimethoxy-phenyl)-acetic acid ethyl ester.
Compounds of formula I as well as physiologically acceptable salts thereof and/or physiologically acceptable esters thereof are preferred, with the compounds of formula I being particularly preferred.
Preferred compounds of formula I are those, wherein only one of R2 and R3 represents hydrogen. Another preferred embodiment of the present invention are compounds as described above, wherein R1 represents ethyl.
In a further preferred embodiment the invention relates to compounds as described above in which R2 represents hydrogen, 2-hydroxy-ethoxy, or 2-(2,2,2-trichloro-ethoxycarbonyloxy)-ethoxy. Compounds in which R2 represents hydrogen are preferred and such in which R2 represents 2-hydroxy-ethoxy are also preferred. Compounds in which R3 represents hydrogen are preferred, as well as compounds in which R3 represents ethoxy and compounds in which R3 represents tetrahydrofuran-3-yloxy.
The invention embraces especially compounds in accordance with the above definitions in which R4 represents hydrogen, alkyl or aryl-alkyl, with hydrogen, ethyl, iso-propyl, butyl, iso-butyl or benzyl being preferred, with hydrogen being more preferred and with ethyl also being more preferred.
Moreover, the invention relates especially to compounds as defined above in which R5 represents hydrogen, hydroxy, ethoxycarbonyl, 2,2,2-trichloro-ethoxycarbonyl, methoxycarbonyl, 4-fluoro-phenyloxycarbonyl, benzyloxycarbonyl, 2-methoxy-ethoxycarbonyl, 2-isopropyl-5-methyl-cyclohexyloxycarbonyl, prop-2-ynyloxycarbonyl, 5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxycarbonyl, benzoyloxy, ethylaminocarbonyloxy, phenylaminocarbonyloxy, benzoyl, 3-fluoro-benzoyl, 4-fluoro-benzoyl, 2,4-difluoro-benzoyl, 3,4-dimethoxy-benzoyl, 3,5-dimethoxy-benzoyl, 4-methyl-benzoyl, 4-trifluoromethyl-benzoyl, phenylaminocarbonyl, or isobutoxy-carbonyl. Compounds as defined above wherein R5 is hydrogen are particularly preferred as well as compounds in which R5represents hydroxy, compounds in which R5 represents benzoyl, and compounds in which R5 represents 2,2,2-trichloro-ethoxycarbonyl. Another preferred embodiment relates to compounds in which X represents fluorine.
In context with the present invention, compounds according to the definitions given above characterised by formula Ia 
wherein R1, R2, R3, R4, R5, and X have the significances given above are also preferred.
In particular, preferred compounds are the compounds of formula I described in the examples as individual compounds in the form of the free acids, their esters as well as hydrates or solvates and physiologically usable salts thereof.
Preferred individual compounds are those selected from the group consisting of:
(RS)-(4-Carbamimidoyl-phenylamino)-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester hydrochloride,
(RS)-(4-Carbamimidoyl-phenylamino)-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid,
(S)-(4-Carbamimidoyl-phenylamino)-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid,
(R)-(4-Carbamimidoyl-phenylamino)-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid,
(RS)-[5-Ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid ethyl ester,
(S)-[5-Ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid ethyl ester,
(R)-[5-Ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid ethyl ester,
(RS)-[5-Ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid sodiumchloride,
(RS)-[4-(Amino-ethoxycarbonylimino-methyl)-phenylamino]-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester,
(RS)-{4-[Amino-(2,2,2-trichloro-ethoxycarbonylimino)-methyl]-phenylamino}-{5-ethoxy-2-fluoro-4-[2-(2,2,2-trichloro-ethoxycarbonyloxy)-ethoxy]-phenyl}-acetic acid ethyl ester,
(RS)-{4-[Amino-(2,2,2-trichloro-ethoxycarbonylimino)-methyl]-phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester,
(S)-{4-[Amino-(2,2,2-trichloro-ethoxycarbonylimino)-methyl]-phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester,
(R)-{4-[Amino-(2,2,2-trichloro-ethoxycarbonylimino)-methyl]-phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester,
(RS)-[4-(Amino-methoxycarbonylimino-methyl)-phenylamino]-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester,
(RS)-{4-[Amino-(4-fluoro-phenoxycarbonylimino)-methyl]-phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester,
(RS)-[4-(Amino-benzyloxycarbonylimino-methyl)-phenylamino]-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester,
(RS)-{4-[Amino-(2-methoxy-ethoxycarbonylimino)-methyl]-phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester,
{4-[Amino-[1R-(2S-isopropyl-5R-methyl-cyclohexyl)oxycarbonylimino]-methyl]-phenylamino}-xcex1(RS)-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester,
(RS)-[4-(Amino-prop-2-ynyloxycarbonylimino-methyl)-phenylamino]-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester,
(RS)-{4-[Amino-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxycarbonylimino)-methyl]-phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester,
(R,S)-xcex1-[[4-[[(Benzoyloxy)amino]iminomethyl]phenyl]amino]-5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)-benzeneacetic acid ethyl ester,
(R,S)-5-Ethoxy-xcex1-[[4-[[[[(ethylamino)carbonyl]oxy]amino]iminomethyl]phenyl]amino]-2-fluoro-4-(2-hydroxyethoxy)-benzeneacetic acid ethyl ester,
(R,S)-5-Ethoxy-2-fluoro-4-(2-hydroxyethoxy)-xcex1-[[4-[imino[[[(phenylamino)carbonyl]oxy]amino]methyl]phenyl]amino]-benzeneacetic acid ethyl ester,
(RS)-{4-[Amino-(4-fluoro-benzoylimino)-methyl]-phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester,
(RS)-[4-(Amino-benzoylimino-methyl)-phenylamino]-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester,
(S)-[4-(Amino-benzoylimino-methyl)-phenylamino]-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester,
(R)-[4-(Amino-benzoylimino-methyl)-phenylamino]-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester,
(RS)-[4-(Amino-phenylcarbamoylimino-methyl)-phenylamino]-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester,
(RS)-[5-Ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid butyl ester,
(S)-[5-Ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid butyl ester,
(R)-[5-Ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid butyl ester,
(RS)-[5-Ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid isopropyl ester,
(S)-[5-Ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid isopropyl ester,
(R)-[5-Ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid isopropyl ester,
(RS)-[5-Ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid benzyl ester,
(S)-[5-Ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid benzyl ester,
(R)-[5-Ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid benzyl ester,
(RS)-[5-Ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid isobutyl ester,
(S)-[5-Ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid isobutyl ester,
(R)-[5-Ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid isobutyl ester,
(RS)-{4-[Amino-(2,4-difluoro-benzoylimino)-methyl]-phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester,
(RS)-{4-[Amino-(3,5-dimethoxy-benzoylimino)-methyl]-phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester,
(RS)-{4-[Amino-(3,4-dimethoxy-benzoylimino)-methyl]-phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester,
(RS)-{4-[Amino-(3-fluoro-benzoylimino)-methyl]-phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester,
(RS)-{4-[Amino-(4-trifluoromethyl-benzoylimino)-methyl]-phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester,
(RS)-{4-[Amino-(4-methyl-benzoylimino)-methyl]-phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester,
(R)-(4-Carbamimidoyl-phenylamino)-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid,
(S)-(4-Carbamimidoyl-phenylamino)-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid,
(RS)-(3,5-Diethoxy-2-fluoro-phenyl)-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid ethyl ester,
(R)-(3,5-Diethoxy-2-fluoro-phenyl)-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid ethyl ester,
(S)-(3,5-Diethoxy-2-fluoro-phenyl)-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid ethyl ester,
(RS)-(3,5-Diethoxy-2-fluoro-phenyl)-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid,
(R)-(3,5-Diethoxy-2-fluoro-phenyl)-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid,
(S)-(3,5-Diethoxy-2-fluoro-phenyl)-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid,
(RS)-[4-(Amino-ethoxycarbonylimino-methyl)-phenylamino]-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid ethyl ester,
(RS)-{4-[Amino-(4-fluoro-phenoxycarbonylimino)-methyl]-phenylamino}-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid ethyl ester,
(RS)-{4-[Amino-(2,2,2-trichloro-ethoxycarbonylimino)-methyl]-phenylamino}-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid ethyl ester,
(RS)-{4-[Amino-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxycarbonylimino)-methyl]-phenylamino}-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid ethyl ester,
(RS)-[4-(Amino-methoxycarbonylimino-methyl)-phenylamino]-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid ethyl ester,
(RS)-[4-(Amino-phenoxycarbonylimino-methyl)-phenylamino]-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid ethyl ester,
(RS)-[4-(Amino-isobutoxycarbonylimino-methyl)-phenylamino]-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid ethyl ester,
(RS)-{4-[Amino-(4-fluoro-benzoylimino)-methyl]-phenylamino}-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid ethyl ester,
(RS)-(3,5-Diethoxy-2-fluoro-phenyl)-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid butyl ester,
(RS)-(3,5-Diethoxy-2-fluoro-phenyl)-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid isopropyl ester,
(RS)-[5-Ethoxy-2-fluoro-3-[(R)-tetrahydro-furan-3-yloxy]-phenyl]-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid ethyl ester,
(R)-[5-Ethoxy-2-fluoro-3-[(R)-tetrahydro-furan-3-yloxy]-phenyl]-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid ethyl ester,
(S)-[5-Ethoxy-2-fluoro-3-[(R)-tetrahydro-furan-3-yloxy)-phenyl]-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid ethyl ester,
(RS)-(4-Carbamimidoyl-phenylamino)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydro-furan-3-yloxy]-phenyl]-acetic acid ethyl ester hydrochloride, (RS)-(4-Carbamimidoyl-phenylamino)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydro-furan-3-yloxy]-phenyl]-acetic acid,
(R)-(4-Carbamimidoyl-phenylamino)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydro-furan-3-yloxy]-phenyl]-acetic acid,
(S)-(4-Carbamimidoyl-phenylamino)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydro-furan-3-yloxy]-phenyl]-acetic acid,
(RS)-(4-Carbamimidoyl-phenylamino)-[5-ethoxy-2-fluoro-3-[(S)-tetrahydro-furan-3-yloxy]phenyl]-acetic acid ethyl ester hydrochloride,
(RS)-(4-Carbamimidoyl-phenylamino)-[5-ethoxy-2-fluoro-3-[(S)-tetrahydro-furan-3-yloxy]-phenyl]-acetic acid,
(R)-(4-Carbamimidoyl-phenylamino)-[5-ethoxy-2-fluoro-3-[(S)-tetrahydro-furan-3-yloxy]-phenyl]-acetic acid, and
(S)-(4-Carbamimidoyl-phenylamino)-[5-ethoxy-2-fluoro-3-[(S)-tetrahydro-furan-3-yloxy]-phenyl]-acetic acid.
Particularly preferred are those compounds selected from the group consisting of
(R)-(4-Carbamimidoyl-phenylamino)-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid,
(R)-(4-Carbamimidoyl-phenylamino)-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid,
(R)-(4-Carbamimidoyl-phenylamino)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydro-furan-3-yloxy]-phenyl]-acetic acid,
(R)-[5-Ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid ethyl ester,
(R)-{4-[Amino-(2,2,2-trichloro-ethoxycarbonylimino)-methyl]-phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester,
(R)-[4-(Amino-benzoylimino-methyl)-phenylamino]-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester,
(R)-[5-Ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid butyl ester,
(R)-[5-Ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid isopropyl ester,
(R)-[5-Ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid benzyl ester, and
(R)-[5-Ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid isobutyl ester.
Other particularly preferred compounds are those selected from the group consisting of
(R)-(4-carbamimidoyl-phenylamino)-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester,
(R)-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid, and
(RS)-[5-ethoxy-2-fluoro-3-[(S)-tetrahydro-furan-3-yloxy]-phenyl]-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid ethyl ester.
Another preferred compound is (S)-(4-carbamimidoyl-phenylamino)-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester.
Physiologically acceptable salts of the compounds individually mentioned above also constitute a preferred embodiment of the present invention.
Further preferred compounds in accordance with the definitions given above are those, wherein R3 is not alkoxy if R5 is hydrogen.
The invention further relates to a process for the manufacture of compounds of formula I, which process comprises converting the nitrile group in a compound of formula II 
wherein R1, R2, R3, R4 and X have the significances given above, into a carbamimidoyl group or into a N-hydroxy-carbamimidoyl group and, if desired, modifying a reactive group present in an obtained compound of formula I and, if desired, converting a compound of formula I obtained into a physiologically compatible salt or converting a salt of a compound of formula I into the free acid or base.
Further the invention relates to compounds of formula I as defined above, when manufactured according to this process. In another embodiment the invention relates to compounds of formula II, wherein R1, R2, R3, R4 and X have the significances given above.
The conversion of the nitrile group in a compound of formula II into a carbamimidoyl group xe2x80x94C(NH)NH2 or a N-hydroxy-carbamimidoyl group xe2x80x94C(NOH)NH2 can be carried out according to methods known per se. For example, the conversion into a N-hydroxycarbamimidoyl group can be performed by dissolving a compound of formula II in a solvent, such as DMF, ethanol or methanol, treating the solution with hydroxylamine or a salt of hydroxylamine with an inorganic acid, such as hydroxylamine hydrochloride, and thereafter with a base, such as diisopropylethylamine or triethylamine, sodium hydride or sodium methanolate, conveniently at a temperature up to 80xc2x0 C.
The conversion of the nitrile group into a carbamimidoyl group can be carried out e.g. by treating a compound of formula II in a solvent, such as ethanol or methanol, or a solvent mixture, such as chloroform and methanol or chloroform and ethanol, with a dry stream of hydrogen chloride, conveniently at a temperature below 10xc2x0 C., thereafter treating the reaction solution with a solvent, such as diethyl ether, and filtering off the precipitated iminoether. The thus-obtained material is treated in a solvent, such as methanol or ethanol, either with gaseous ammonia or an ammonium salt, such as ammonium chloride, conveniently at a temperature up to 80xc2x0 C. Alternatively, the solution containing the iminoether can be evaporated and the residue can be treated with gaseous ammonia or an ammonium salt in methanol or ethanol. In an analogous manner, the iminoether can be converted into a N-hydroxy-carbamimidoyl compound of formula I with hydroxylamine or a salt thereof in the presence of a base.
As modifications of functional groups present in a compound of formula I there come into consideration especially the conversion of a N-hydroxy-carbamimidoyl group into a carbamimidoyl group, the esterification of a carboxy group, the saponification of an ester group and the cleavage of an ether group, such as an arylalkyl ether group, e.g. the benzyl ether group. All of these reactions can be carried out according to methods known per se.
For the conversion of a N-hydroxy-carbamimidoyl group into a carbamimidoyl group, an amidoxime of formula I can be hydrogenated in a solvent, such as ethanol, methanol, dioxan, THF or glacial acetic acid, or a solvent mixture, such as ethanol and glacial acetic acid, with hydrogen and a catalyst, such as palladium, platinum or nickel. In so doing, other reactive groups present in the compound of formula I and reactive towards the reducing agent can be modified.
By reacting a compound of formula I in which R5 represents hydrogen with a suitable chloroformic acid ester wherein a hydroxy or carboxy group can be present in protected form, in a solvent, such as dichloromethane, dioxane or DMF, or a solvent mixture, such as dichloromethane and water or ethyl acetate and water, in the presence of an organic base, such as pyridine or triethylamine, or an inorganic base, such as sodium hydroxide, sodium carbonate or potassium hydrogen carbonate, there is obtained the corresponding compound of formula I in which R5 as described above represents alkoxycarbonyl, halogenalkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, alkoxyalkoxycarbonyl, cycloalkyloxycarbonyl, alkynyloxycarbonyl or a similar group comprising an oxycarbonyl structure. Analogously, a compound of formula I in which R5 represents hydrogen can be converted with a suitable p-nitrophenyl carbonate into the corresponding compound of formula I in which R5 as described above represents a group comprising an oxycarbonyl structure. The reaction can e.g. be carried out by treating the p-nitrophenyl carbonate in THF and DMF firstly with N,N-diisopropylethylamine and then with a compound of formula I in which R5 represents hydrogen.
By reacting a compound of formula I in which R5 represents hydrogen with an acyl chloride, such as an aroyl chloride, there is obtained the corresponding compound of formula I in which R5 as defined before represents an acyl group. The reaction can e.g. carried out by treating the acyl chloride in THF and DMF firstly with N,N-diisopropylethylamine and then with a compound of formula I in which R5 represents hydrogen.
By reacting a compound of formula I in which R5 represents hydroxy with an acyl halide there can be obtained a compound of formula I in which R5 as defined above represents arylcarbonyloxy or a similar group comprising a carbonyloxy structure. The reaction can e.g. be carried out by treating the acyl chloride in THF and DMF firstly with N,N-diisopropylethylamine and then with a compound of formula I in which R5 represents hydroxy.
By reacting a compound of formula I in which R5 represents hydrogen with a suitable isocyanate there can be obtained a compound of formula I in which R5 as described above represents a group comprising an aminocarbonyl structure. The reaction can be carried out by reacting a compound of formula I in which R5 represents hydrogen with a suitable isocyanate in THF and DMF in the presence of triethylamine.
By reacting a compound of formula I in which R5 represents hydroxy with a suitable isocyanate there can be obtained a compound of formula I in which R5 as described above represents a group comprising an aminocarbonyloxy structure. The reaction can be carried out by reacting a compound of formula I in which R5 represents hydroxy with a suitable isocyanate in THF.
The compounds of formula II can be prepared according to general methods known per se, e.g. as described hereinafter and/or as described in the Examples or in analogy to these methods. For example, an aldehyde of formula III 
in which R1, R2, R3 and X have the significances given above, can be reacted with a p-aminobenzonitrile of formula IV 
and benzylisonitrile, toluenesulfonylmethylisonitrile, or morpholinoethylisocyanide, and a primary alkanol such as methanol or ethanol, in the presence of boron trifluoride etherate. Hydrolysis of the resulting iminoether with water yields a compound of formula II in which R4 represents methyl or ethyl. By hydrolysis of the ester group R4, e.g. by treatment with LiOH in tetrahydrofuran, there is obtained a compound of formula II in which R4 represents hydrogen.
Further reactions for the preparation of compounds of formula II:
By reaction of compounds of formula II in which R1 together with the connecting oxygen atom and/or one or more of R2 -R3 represent hydroxy:
with an alkylating agent such as an alkyl bromide, alkyl iodide or alkyl mesylate in the presence of a base such as potassium carbonate or caesium carbonate in a solvent such as DMF or acetone, or
by a Mitsunobu reaction with an alkohol in the presence of DEAD, DIAD, or di-tert.-butyl-azodicarboxylate, and triphenylphosphine in a solvent such as THF or dioxane, there are obtained compounds of formula II in which the hydroxy group is converted to an alkoxy group.
Compounds of formula III are known per se. They can be obtained e.g. by reacting compounds of formula III in which R1 together with the connecting oxygen atom and/or one or more of R2-R3:
represent a hydroxy group
with an alkylating agent such as e.g. ethyl bromide in the presence of a base such as potassium carbonate oder caesium carbonate in a suitable solvent such as DMF or acetone, preferably at an elevated temperature, or
in a Mitsunobu reaction with an alcohol in the presence of DEAD, DIAD, or di-tert.-butyl-azodicarboxylate, and triphenylphosphine in a solvent such as THF or dioxane, to give compounds of formula III in which the hydroxy group is substituted by an alkoxy group;
represent a silyloxy group
with an alkylating agent such as e.g. an alkyl bromide in a suitable solvent such as e.g. DMF in the presence of potassium fluoride, to give compounds of formula III in which the silyloxy group is substituted by an alkoxy group.
Starting materials for the preparation of compounds of formula III are either commercially available or can be prepared by methods known in the art.
Insofar as their preparation is not described in the Examples, the compounds of formulae I, II, III and IV can be prepared according to analogous methods or according to the methods set forth above.
The compounds of formula I are active compounds and inhibit the formation of coagulation factors Xa, IXa and thrombin induced by factor VIIa and tissue factor or are derivatives which are converted under physiological conditions to such active compounds. These compounds consequently influence both platelet aggregation which is induced by these factors and plasmatic blood coagulation. They therefore inhibit the formation of thrombi and can be used for the control or prevention of diseases, such as thrombosis, apoplexy, cardiac infarction, inflammation and arteriosclerosis. Furthermore, these compounds have an effect on tumour cells and prevent metastases. They can therefore also be employed as antitumour agents.
Accordingly, the present invention also relates to pharmaceutical preparations comprising a compound as described above and a pharmaceutically acceptable carrier and/or adjuvant.
The invention likewise embraces compounds as described above for use as therapeutic active substances. The subject compounds can inhibit formation of clotting factors Xa, IXa and thrombin induced by factor VIIa and tissue factor. Such inhibitors can be used as therapeutic active substances for the treatment or prevention of thrombosis, apoplexy, cardiac infarction, inflammation and/or arteriosclerosis and/or as an antitumour agent.
In another preferred embodiment, the invention relates to a method for the therapeutic and/or prophylactic treatment of thrombosis, apoplexy, cardiac infarction, inflammation, arteriosclerosis and/or tumor, which method comprises administering a compound as defined above to a human being or animal.
The invention also embraces the use of a compound as defined above for the treatment or prophylaxis of thrombosis, apoplexy, cardiac infarction, inflammation, arteriosclerosis and/or tumor.
The invention also relates to the use of a compound as described above for the preparation of medicaments for the treatment or prevention of thrombosis, apoplexy, cardiac infarction, inflammation and arteriosclerosis or of antitumor agents. Such medicaments comprise a compound as described above.
The inhibition of the amidolytic activity of factor VIIa/tissue factor complex by the compounds in accordance with the invention can be demonstrated with the aid of a chromogenic peptide substrate as described hereinafter.
The measurements were carried out on microtitre plates at room temperature. To this end, 100 xcexcl of a solution of 26 nM of tissue factor, 9 nM of soluble factor VIIa and 8 mM of calcium chloride were added to 25 xcexcl of a solution of the inhibitor in a buffer [pH 7.5, 100 mM, comprising 0.14M NaCl, 0.1M N-(2-hydroxyethyl)piperazine-Nxe2x80x2-(2-ethanesulphonic acid) (HEPES), 0.5 mg/l of fatty-acid-free BSA (bovine serum albumin) and 0.05% NaN3] in each well of the plate. After an incubation time of 15 minutes the reaction was started by the addition of 50 xcexcl of chromogenic substrate Chromozym-tPA (3.5 mM, MeSO2-D-Phe-Gly-Arg-paranitroanilide) and the hydrolysis of the substrate was followed spectrophotometrically on a kinetic microtitre plate reader over 10 minutes. Using the plot of the inhibition curves, the Ki values were determined according to the method described in Biochem. J. 55, 1953, 170-171.
The activity of the low molecular weight substances can, moreover, be characterized in the xe2x80x9cprothrombin timexe2x80x9d (PT) clotting test. The substances are prepared as a 10 mM solution in DMSO or DMSO/0.1M HCl (DHCl) and thereafter made up to the desired dilution in the same solvent. Thereafter, 0.25 ml of human plasma (obtained from whole blood anticoagulated with {fraction (1/10)} volume of 108 mM Na citrate) was placed in the instrument-specific sample container. In each case 5 xcexcl of each dilution of the substance-dilution series was then mixed with the plasma provided. This plasma/inhibitor mixture was incubated at 37xc2x0 C. for 2 minutes. Thereafter, there were pipetted to the semi-automatic device (ACL, Automated Coagulation Laboratory (Instrument Laboratory)) 50 xcexcl of plasma/inhibitor mixture in the measurement container. The clotting reaction was initiated by the addition of 0.1 ml of Innovin(copyright) (recombinant human tissue factor combined with calcium buffer and synthetic phospholipids (Dade Behring(copyright), Inc.). The time up to the fibrin cross-linking was determined photooptically from the ACL. The inhibitor concentration, which brought about a doubling of the PT clotting time, was determined by means of a graph.
The Ki value of the active compounds of the present invention preferably amounts to about 0.1 to 500 nM, especially about 0.1 to 150 nM. The PT values preferably amount to about 0.1 to 10 xcexcM, especially to about 0.1 to 5 xcexcM.
As mentioned earlier, medicaments containing a compound of formula I, a solvate or a salt thereof also form an object of the present invention, as does a process for the production of such medicaments which comprises bringing one or more of such compounds, solvates or salts and, if desired, other therapeutically useful substances into a galenical administration form. These medicaments can be administered orally, e.g. in the form of dragxc3xa9es, hard and soft gelatine capsules, solutions, emulsions or suspensions, or rectally, for example in the form of suppositories, or as a spray. However, administration can also be carried out parenterally, e.g. in the form of injection solutions.
For the production of tablets, coated tablets, dragxc3xa9es and hard gelatine capsules, the active ingredient can be mixed with pharmaceutically inert, inorganic or organic excipients. Suitable excipients for tablets, coated tablets, dragxc3xa9es and hard gelatine capsules are, for example, lactose, maize starch or derivatives thereof, talc, stearic acid or its salts. Suitable excipients for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols; depending on the nature of the active ingredient no excipients are, however, usually required in the case of soft gelatine capsules. Suitable excipients for the production of solutions and syrups are e.g. water, polyols, sucrose, invert sugar and glucose; suitable excipients for injection solutions are e.g. water, alcohols, polyols, glycerol and vegetable oils, and suitable excipients for suppositories are natural and hardened oils, waxes, fats, semi-liquid or liquid polyols. In addition, the pharmaceutical preparations can also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, coating agents or antioxidants.
The dosage of the active ingredient for the control or prevention of the illnesses mentioned above can vary within wide limits and will, of course, be adapted to the individual requirements in each particular case. In general, in the case of oral or parenteral, e.g. intravenous or subcutaneous, administration, a dose of about 0.1 to 20 mg/kg, preferably about 0.6 to 5 mg/kg, per day should be adequate for adults, although the upper limit which has just been mentioned may be exceeded or the dose may be lower when this is shown to be indicated.
The following examples shall illustrate in more detail the present invention and preferred embodiments thereof but are not intended to limit the scope of the invention.